A large body of evidence has accumulated that cancer occurs through a progression of multiple independent stages. Certain tissue culture cell lines have been used to identify genetic elements (oncogenes) which can induce a transition from a non-tumorigenic stage to one which is tumorigenic. Not all the genetic factors involved in malignant progression can be accounted for in terms of the expression of activated oncogenes. I have developed a human cell model in which stages of progression have been identified and can be used to study how oncogenes and potentially other genes are able to affect these changes. PA-1 human teratocarcinoma cells show progression as they are passaged in culture. Early passage cells are non-tumorigenic in athymic nude mice while late passage cells readily form tumors. This transition is induced by an activated N-ras oncogene. Metastatic PA-1 cells were derived from late passage tumor cells. Since all of these stages of PA-1 cell progression are essentially diploid, the progression cannot be accounted for by gross chromosomal aberrations. PA-1 cells provide a genetically stable model to analyze the molecular basis of malignant progression. I will employ multiple molecular biological approaches to identify the genetic elements which affect or are affected by the progression of malignancy.